Submissions for variant NM_000059.4(BRCA2):c.1354C>A (p.Leu452Ile)

dbSNP: rs80358424

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112911	SCV000244420	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0003
Ambry Genetics	RCV000561047	SCV000665329	likely benign	Hereditary cancer-predisposing syndrome	2024-10-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000561047	SCV000906886	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 452 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_003665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496565	SCV001363258	uncertain significance	not specified	2019-08-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1354C>A (p.Leu452Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247634 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1354C>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. The variant has been predicted to be benign based on multifactorial likelihood analysis (Whiley_2014). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two classified as VUS while one classified as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001410482	SCV001612531	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112911	SCV004846907	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 452 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_003665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112911	SCV000145857	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112911	SCV000297503	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-11-18	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496565	SCV000587593	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research